1. Field of the Invention
This invention relates to apparatus for the measurement of the dissolution behavior of solid soluble materials in particular solvents. More particularly, the invention relates to a cell for the measurement of the dissolution behavior of drugs.
When dissolution is the rate limiting step in drug absorption, correlations between in vivo drug levels and in vitro dissolution test data are essential if the latter are to serve a useful quality control or dosage form design and development function. Presently known devices for in vitro dissolution testing are poorly designed so as to be fluid-dynamically ill-defined and/or unstable, and/or are not capable of providing unambiguous dissolution information on the heterodisperse multiparticulate solids which are typical of solid drug dosage forms. The invention described herein enables one to subject various sized particles from such dosage forms to well defined solvent flow conditions which are unambiguously related to drug particle size.
2. Description of the Prior Art
Dissolution testing of drugs has been conducted in numerous apparatus variations and types. This equipment represents variations of a relatively few general classes, having well documented design features and primarily falling into two categories: flow-through cells and stirred vessels.
The principal stirred vessel methods are the rotating basket and paddle methods of the USP/NF and the stationary basket--rotating filter method. The former consists of a cylindrical vessel with a rounded bottom having a vertically mounted, rotating screen basket or paddle at the central axis of the vessel. In the latter case, a similar vessel is used, agitation being produced by the vertically mounted and rotating sampling filter at the vessel axis. The dosage unit is placed in a stationary screen basket to one side of the filter. In all three cases, mixing of the dissolution solvent is poor and dissolution of larger particles is favored over smaller. Large particles retained in the baskets are subject to more rapid dissolution. Moreover, small particles tend to lodge between larger particles on the vessel bottom and are shielded from solvent flow. Smaller particles entrained in the solvent, and moving with it, will also experience reduced flow past their surfaces.
Flow-through cells generally provide only gravity restraint of particles in an upward solvent flow, but have filters at both ends preventing particles from leaving the cell. As with the stirred vessel, entrainment of smaller particles in the flow field will diminish their dissolution rate. The largest and smallest particles, immobilized by their weight or by the barrier filter, respectively, will experience essentially the same solvent flow. Alternatively some cells immobilize all particles by sandwiching them tightly between two filters or screens. The USP/NF tablet disintegration apparatus consisting of a vertically oscillating basket arrangement in a solvent bath has been used for dissolution testing. One commercial device subjects the dosage form to a tumbling/kneading action within a bed of uniform sized glass balls, which presumably simulates the action of the GI tract.
Any of the above described devices may be used with simulated gastric or intestinal fluids. Only the sandwich type cell provides a closely defined solvent flow as a function of particle size. The fluid-dynamics of none of the methods favor dissolution of the smaller particles over the larger. Recent studies have correlated data obtained by the three principal stirred vessel methods, indicating that the data obtained provide the same information. Where correlations have not been found, differences in dosage unit disintegration may be responsible.
The Kelvin effect and the large divergence of concentration gradient fields surrounding very small particles tend to favor their rapid dissolution under most conditions. Where the morphology of particles in a polydisperse system is size independent, these may be the only effects. However, various dosage unit formulations may cause differences in the relative intrinsic solubilities and dissolution rates of particles of different sizes. This requires that the fluid-dynamics of dissolution be controlled as a function of particle size. Furthermore, depending upon the resolution desired, at least two procedures, which produce well defined and linearly independent functional relationships between particle size and dissolution fluid-dynamics, are needed. Thus, a single dissolution test procedure cannot be expected to produce data which correlate adequately with the in vivo behavior of different formulations. The present invention provides an essential set of alternate procedures.